The skin, often referred to as the largest organ of the human body, acts as a waterproof, insulating shield, protecting the body against extremes of temperature, damaging sunlight, harmful chemicals and pathogens. It helps to regulate body temperature and evaporation, and acts as a huge sensor packed with nerves for perceiving and transmitting external stimuli. Skin is made up of two primary layers. The outermost is the epidermis, which consists mainly of highly organized keratinocytes. Complex cellular junctions (desmosomes) connect the keratinocytes to each other, which secrete keratin proteins and lipids forming an extracellular matrix that provides mechanical strength to the skin. The epidermis is bonded to a deeper skin layer below known as the dermis which consists of connective tissue and provides tensile strength and elasticity to the skin through an extracellular matrix composed of collagen fibrils, microfibrils, and elastic fibers, embedded in proteoglycans. Epidermis and dermis are separated by a thin layer called the basement membrane. The dermal-epidermal junction (DEJ) is the area of tissue that joins the epidermal and the dermal layers of the skin.
The autoimmune bullous diseases (AMDB) are a group of skin disorders that primarily affect the skin and mucous membranes. In AMDB, the host immune system disrupts intercellular adhesion molecules or components of the basement membrane in the skin and mucosal surfaces, typically leading to blister formation. Because the intact skin is vital for protecting the body against dehydration and infections, AMDB are often associated with a high degree of morbidity and may be life threatening.
AMDB can be subdivided into four major groups. Intraepidermal blistering diseases (the ‘pemphigus group’) are characterized by the loss of intercellular connections such as desmosomes, the deposition of immunoreactants at the intercellular junctions of the keratinocytes and the formation of intraepidermal blisters resulting from cell-cell dysadhesion. Typical intraepidermal autoimmune blistering diseases include pemphigus vulgaris (PV) and pemphigus foliaceus (PF). The remainder of the diseases is characterized by subepidermal blister formation resulting from cell-matrix dysadhesion and the deposition of autoantibodies at the dermal-epidermal junction (DEJ). The ‘pemphigoid group’ includes bullous pemphigoid (BP), mucous membrane pemphigoid (MMP), pemphigoid gestationis, mucous membrane pemphigoid, and linear IgA disease. Lichen planus pemphigoides is sometimes considered a rare variant of BP. The other two groups include epidermolysis bullosa acquisita (EBA), and dermatitis herpetiformis (Mihai and Sitaru, 2007). Bullous systemic lupus erythematosus (BSLE) is a generalized subepidermal blistering disease occurring in patients with systemic lupus erythematosus.
The disruption of structural elements in the skin leading to the typical blister formation in AMDB has been mainly attributed to autoreactive antibodies. Besides, the complement system and autoreactive T cells are thought to be involved in AMDB pathogenesis (Liu and Rubinstein (2008)). Most AMDB are associated with tissue-bound and circulating autoreactive antibodies of the IgG class that typically interact through their Fc portions with factors of the innate immune system, such as the complement system and inflammatory cells, and trigger downstream signaling cascades that ultimately result in tissue destruction (Sitaru et al., 2007). Fc gamma receptors (FcγRs) play a key role in mediating the effector functions of autoreactive IgG antibodies in AMDB.
FcγRs belong to the family of Fc receptors (FcRs) which are crucial for defending the human organism against infections. In general, activating FcγRs and inhibiting FcγRs are to be distinguished. Of the three main FcγRs in humans, FcγRI can bind monomeric IgG, whereas FcγRII and FcγRIII bind to multivalent immune complexes (ICs) composed of antibodies and antigens. (Takai (2002)). Effector functions triggered by FcγRs include, depending on the expressed FcR type and associated proteins, endocytosis with subsequent neutralization of the pathogens and antigen presentation, antibody-dependent cellular cytotoxity (ADCC), secretion of mediators or the regulation of antibody production (Fridman et al. (1992), van de Winkel and Capel (1993)).
One example for the unpredictability of treatment success is Rituximab. The antibody recognizes the CD20-antigen which is exclusively expressed on B cells. After binding to the target Rituximab mediates killing of the B cells with the help of the immune system. Rituximab has been developed for the treatment of B cell lymphoma but since then has been used also for the treatment of autoimmune diseases with an involvement of B cells that are known to produce the pathogenic autoantibodies. A physician familiar with the treatment of autoimmune diseases would certainly consider ITP, SLE or ANCA associated vasculitis as treatable with Rituximab due to their considerable level of autoantibodies. However, treatment success for SLE which is characterized by high levels of autoantibodies could not be demonstrated in two clinical studies (Coca and Sanz (2009)). Similarly, in ANCA associated vasculitis only two third of the patients do respond adequately to Rituximab treatment (Stone (2010)) while in ITP 60% do not respond (Patel (2010)). On the other hand, Rituximab could demonstrate efficacy in multiple sclerosis (Hauser (2008)) and Diabetes type I (Pescowitz (2009)), with both diseases not predominated by considerable levels of autoantibodies
To date, conventional AMDB treatment commonly consists of immunosuppressive and anti-inflammatory agents, often at high dosages, and treatment of skin lesions. Unfortunately, many of the drugs used to treat this disease have serious side effects, and patients must be monitored closely for infection, renal and liver function abnormalities, electrolyte disturbances, hypertension, diabetes, anemia, and gastrointestinal bleeding (Mutasim (2007)).
The technical problem underlying the present invention can thus be seen in the provision of an alternative means and method for treating AMDB.